In the previous funding period, we have used the SIV infection/rhesus macaque animal model to investigate factors contributing to CMV pathogenesis in AIDS. In the next grant period, we propose to examine mechanisms of loss of CMV-specific immunity in AIDS. We hypothesize that SIV-mediated loss of CMV-specific CD4 v T cell help is necessary for loss or dysfunction of CMV-specific CD8 v T lymphocytes and memory B lymphocytes in rhesus macaques that develop AIDS. The SIV-induced loss of immune control of latent CMV infection may be due to a combination of destruction, impaired differentiation or effector function, and impaired homing of CMV-specific lymphocytes to tissue sites of CMV reactivation. Insight into mechanisms by which SIV infection affects CMV-specific immune responses will be valuable for understanding how immunological memory is disrupted in HIV-infected humans. Our specific aims are as follows: Specific Aim #1: To investigate whether SIV infection of CMV-specific CD4 + T lymphocytes is a predictor of their decline in rhesus macaques with AIDS. Specific Aim #2: To determine whether the SIV-related decline in CMV-specific CD8 +T lymphocyte responses is secondary to depletion and/or functional anergy associated with loss of CD4 + T cell help. Specific Aim #3: To examine mechanisms of restoration of CMV-specific immunity in SIV-infected macaques treated with HAART.